General research focus
Cancer cells develop a variety of metabolic strategies to cope with the harsh conditions of their microenvironment often characterized by hypoxia, limited nutrient bioavailability and exposure to anticancer treatments. Metabolic heterogeneity further arises from fluctuations of these conditions and the existence of well-supplied tumor areas adjacent to poorly supplied ones. These conditions select a repertoire of possible cellular adaptations, including switching from an oxidative to a glycolytic metabolism, using a variety of metabolites in addition to glucose, optimizing autophagy, enslaving or even cannibalizing nearby cells, cooperating metabolically, stimulating neovascularization and escaping a metabolically inadequate environment during invasive and metastatic processes. Our previous work focused on metabolic cooperation and on the metabolic control of angiogenesis and metastasis. Our general objective is to identify key molecular determinants driving these particular behaviors in order to propose new anticancer strategies targeting tumor metabolism.
Main recent achievements
Metabolic symbiosis in cancer
Cancers are highly heterogeneous metabolically. When studying relationships between different cellular subpopulations in a tumor, we identified a metabolic symbiosis based on the exchange of lactate between hypoxic/glycolytic cancer cells that produce lactate and oxidative cancer cells that use lactate as an oxidative fuel preferentially to glucose. Because oxidative cancer cells are close to tumor-feeding blood vessels and most glycolytic cancer cells reside in poorly supplied areas, the metabolic preference of oxidative cancer cells for lactate improves glucose delivery to hypoxic tumor areas. In the metabolic symbiont, this constitutes a metabolic reward for glycolytic cells. We then investigated the advantages for oxidative cancer cells to engage in such metabolic symbiosis. In these cells, lactate dehydrogenase B (LDHB) catalyzes the conversion of lactate and NAD+ to pyruvate, NADH and H+. If on the one hand we found that pyruvate and NADH produced in this reaction fuel mitochondrial oxidative phosphorylation (OXPHOS)2 and lactate further promotes glutaminolysis, on the other hand we identified that the protons generated by LDHB are necessary for autophagy, which constitutes a major metabolic reward for oxidative cancer cells in the symbiosis. LDHB physically interacts with V-ATPase at the surface of lysosomes and catalyzes the production of protons that fuel this proton pump, resulting in lysosomal acidification, increased autophagic flux and cell survival. In oxidative cancer cells, lactate-induced autophagy would facilitate the recycling of oxidized proteins and organelles. We further identified a same mechanism in glycolytic cancer cells where LDHB uses endogenously produced lactate to produce protons and promote autophagy. For glycolytic cancer cells residing in a metabolically restricted environment, autophagy would primarily serve to provide energetic and biosynthetic precursors. As protons are transferred from the cytosol to lysosomes, LDHB activity further contributes to cytosolic pH homeostasis. Of note, others extended our findings to a form of commensalism where oxidative cancer cells force stromal cells to provide them with lactate. Recently, Hanahan and his collaborators further reported that establishing a metabolic symbiosis based on the exchange of lactate accounts for resistance to antiangiogenic treatments.
While metabolic adaptations allow life with limited resources, cancer cells can also stimulate angiogenesis to improve resource availability. Based on the hypothesis that the glycolytic switch ensuring cancer cell survival under hypoxia precedes the angiogenic switch, we tested the possibility of a glycolytic control of angiogenesis. We found that lactate acts as a signaling agent that activates transcription factor hypoxia-inducible factor-1 (HIF-1) in cancer and endothelial cells and nuclear factor-κB (NF-κB) in endothelial cells. This activity of lactate requires its intracellular oxidation to pyruvate by LDHB in the responding cells and an accumulation of pyruvate that outcompetes 2-oxoglutarate from prolylhydroxylase (PHD) enzymes that control HIF-1 and NF-κB activation. Upon activation by lactate, HIF-1 and NF-κB trigger VEGF, bFGF and IL-8 pro-angiogenic signaling pathways. Thus, lactate produced by glycolytic cancer cells in hypoxic tumor areas diffuses to oxygenated areas where, acting as a hypoxia-mimetic, it stimulates angiogenesis.
Mitochondrial superoxide triggers tumor metastasis
When resources become scarce, another strategy is to leave the environment, which for cancer cells corresponds to local invasion and distant metastasis. Metastasis is generally a late event in clinical cancers, suggesting that metastatic progenitor cells result from selection. Experimentally, we successfully selected superinvasive (in vitro) and supermetastatic (in vivo) cells from various types of weakly metastatic cancer cells. Paired comparisons revealed that both superinvasive and supermetastatic cancer cells gained increased mitochondrial superoxide production during selection, in a concentration window promoting metastasis but not apoptosis. We further found that mitochondrial superoxide activates the TGFβ pathway, which allowed altered mitochondria to stimulate cancer cell migration, invasion, clonogenicity and metastasis. In wild-type models, mitochondria controlled spontaneous metastasis of B16F10 mouse melanoma and triple-negative MDA-MB-231 human breast cancer in mice.
Targeting cancer metabolism for anticancer therapy
A general aim of our team is to translate fundamental findings in new anticancer treatments. The existence of a metabolic symbiosis has been confirmed by independent groups in a variety of human cancers. When analyzing lactate trafficking, we found that lactate exchanges in cancer are mediated by monocarboxylate transporters (MCTs), among which MCT4 is adapted for lactate export by glycolytic cancer cells and MCT1 primarily facilitates lactate uptake by oxygenated cancer and endothelial cells. MCT1 is a druggable target accessible to systemic anticancer therapy. In collaboration with Prof. Olivier Feron, we therefore developed, validated and patented new drugs selectively inhibiting MCT1-dependent lactate uptake. For other applications than cancer, we collaborated with Prof. Véronique Préat to engineer slow-releasing lactate polymers for their ability to stimulate reparative angiogenesis and wound healing. Compared to MCT1 inhibition, LDHB inhibition furthers blocks autophagy in glycolytic cancer cells. We reported that LDHB silencing kills a wide variety of human cancer cells but spares normal differentiated human cells.